Multiple myeloma (MM) is a malignant disorder of differentiated B-cells (plasma cells) and remains incurable. The growth and chemotherapeutic resistance of the MM cells is supported by the bone marrow microenvironment (BMM) through the continuous expression and secretion of chemokines and cytokines. The best-characterized myeloma growth factor is interleukin 6 (IL-6), which is found at high serum levels in MM patients, and has been directly related to the pathogenesis of MM. Consequently, IL-6 production has been identified as a therapeutic target to inhibit MM cell growth and resistance to chemotherapeutics. The goal of the proposal is to generate potent inhibitors of IL-6 production for the use as single agents, or as additives to current therapeutics, to enhance the overall therapeutic outcome of multiple myeloma treatment. Our lab has recently reported a class of small molecular weight scaffolds as potent inhibitors of IL-6 production. The lead compound was capable of inhibiting IL-6 production in human blood at nanomolar concentrations via a mechanism that may be unique among other inhibitors described in the literature. Given the central role of IL-6 in the pathogenesis of multiple myeloma, this proposal is focused on the elucidation of the mode of action and optimization of this class of inhibitors as single agents and adjuvant agents for the treatment of multiple myeloma. The goals of this proposal are to discover the mode of action for IL-6 inhibition, establishing efficacy by using single and adjuvant treatment in multiple myeloma cells and design and execute an enantioselective synthesis to improve access to these potent IL-6 inhibitors. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) remains incurable and MM cells are intrinsically resistant to traditional chemotherapeutic drugs due to the activation of IL-6 mediated growth and survival pathways. We have discovered a potent IL-6 inhibitor capable of reducing IL-6 levels in stimulated human blood and killing MM cells. This project is focused on determining the mode of action of these agents and establishing efficacy in a range of MM cells under conditions that mimic the bone marrow microenvironment.